Doctor of Philosophy

dissertationDespite the advancements in therapies, next-generation sequencing, and our knowledge, breast cancer is claiming hundreds of thousands of lives around the world every year. We have therapy options that work for only a fraction of the population due to the heterogeneity of the disease. It is still overwhelmingly challenging to match a patient with the appropriate available therapy for the optimal outcome. This dissertation work focuses on using biomedical informatics approaches to development of pathwaybased biomarkers to predict personalized drug response in breast cancer and assessment of feasibility integrating such biomarkers in current electronic health records to better implement genomics-based personalized medicine. The uncontrolled proliferation in breast cancer is frequently driven by HER2/PI3K/AKT/mTOR pathway. In this pathway, the AKT node plays an important role in controlling the signal transduction. In normal breast cells, the proliferation of cells is tightly maintained at a stable rate via AKT. However, in cancer, the balance is disrupted by amplification of the upstream growth factor receptors (GFR) such as HER2, IGF1R and/or deleterious mutations in PTEN, PI3KCA. Overexpression of AKT leads to increased proliferation and decreased apoptosis and autophagy, leading to cancer. Often these known amplifications and the mutation status associated with the disease progression are used as biomarkers for determining targeting therapies. However, downstream known or unknown mutations and activations in the pathways, crosstalk iv between the pathways, can make the targeted therapies ineffective. For example, one third of HER2 amplified breast cancer patients do not respond to HER2-targeting therapies such as trastuzumab, possibly due to downstream PTEN loss of mutation or PIK3CA mutations. To identify pathway aberration with better sensitivity and specificity, I first developed gene-expression-based pathway biomarkers that can identify the deregulation status of the pathway activation status in the sample of interest. Second, I developed drug response prediction models primarily based on the pathway activity, breast cancer subtype, proteomics and mutation data. Third, I assessed the feasibility of including gene expression data or transcriptomics data in current electronic health record so that we can implement such biomarkers in routine clinical care

Lisinopril, an angiotensin converting enzyme inhibitor for the treatment of idiopathic oligospermia: a randomized controlled trial

Background: Oligospermia or low concentration of sperm is a common finding in male infertility. Alterations in the expression of angiotensin converting enzyme (ACE) may be one of the mechanisms underlying male infertility and ACE inhibitors may improve the sperm count. The objective was to compare the effects of lisinopril and zinc-folic acid with zinc-folic acid alone on idiopathic oligospermia in infertile males.Methods: This randomized controlled trial was conducted in the Department of Reproductive Endocrinology & Infertility of a medical university from March 2021 to February 2022. A total 78 diagnosed cases of infertile males with idiopathic oligospermia were selected for this study. Eligible men who gave their informed consent were randomly allocated to receive either a combination of low dose lisinopril (2.5 mg) and zinc-folic acid or zinc-folic acid alone for 12 weeks. Pretreatment and post treatment semen parameters, including sperm concentration, sperm motility and total motile sperm count were assessed.Results: There was significant rise in sperm concentration and total motile sperm count in both groups but the mean difference in sperm concentration (2.36±2.04 vs 1.53±1.8 million/ml) and total motile sperm count (11.64±8.28 vs 9.95±6.11 million) were higher in those receiving Lisinopril in addition to zinc folic acid. The percentage increase of sperm count was higher (22.65 vs 16.70 million) in this group. Normalization of sperm count (sperm count ≥15 million/ml) was also higher in this group (18.4% vs 8.3%) with relative risk 2.21, 95% CI (0.648-4.56 %).Conclusions: Lisinopril given orally at the dosage of 2.5 mg/day with zinc-folic acid for 12 weeks appears to be well tolerated among men with oligospermia and improves sperm count by a small margin when compared to zinc folic acid only

Coenzyme q10 and letrozole versus letrozole alone for ovulation induction in polycystic ovary syndrome

Background: Polycystic ovary syndrome (PCOS) is the largest single cause of anovulatory infertility. PCOS is associated with oxidative stress. Coenzyme q10 (Coq10) is an antioxidant that protects the mitochondria from damage caused by either insulin resistance or oxidative free radicals. The objective of the study was to compare the effect of combined Coq10 and letrozole than of letrozole alone for ovulation induction in women with PCOS.Methods: This open label parallel design randomized controlled trial study was conducted on 80 infertile women with PCOS selected for ovulation induction. Eligible women were randomized either to combined Coq10 and letrozole (40 patients, 83 cycles) or letrozole alone (38 patients, 91 cycles). The outcome measures were mature follicles, adequate endometrial thickness, ovulation and pregnancy.Results: Mature follicles (≥18-25 mm) were significantly higher in women given Coq10 at 2nd (74.2% vs 31.3%) and 3rd cycles (83.3% vs 28.6%). Adequate endometrial thickness was significantly higher in women given Coq10 in second (90.3% vs 56.3%) and third cycle (94.4% vs 47.6%). When Coq10 was added to letrozole, ovulation rates were significantly higher (87.1% vs 53.1% in second cycle), (83.3% vs 38.1%, in third cycle). Cumulative pregnancy was 2.37 times (95% CI 1.03-5.48) higher in women having Coq10 in addition to letrozole for ovulation induction. Conclusions: Coq10, as an adjuvant to ovulation induction with letrozole improves ovarian response, ovulation and pregnancy in PCOS women. Combination of Coq10 and letrozole can be tried successfully before a more complicated and expensive treatment such as gonadotrophins and laparoscopic ovarian drilling

Letrozole versus dienogest in endometrioma recurrent after surgery: a randomized controlled trial

Background: Letrozole is a third-generation aromatase inhibitor. As there is aberrant aromatase production by endometriotic stromal cells and the growth and regression of endometriosis is estrogen-dependent, the use of letrozole to reduce the size and symptoms of endometrioma especially in recurrent cases is a promising medical intervention. Dienogest is a fourth-generation progestin which is being used for the treatment of endometriosis due to its antiproliferative and antiangiogenic properties on endometrial tissue. The present study was conducted to compare the effects of letrozole and dienogest on endometrioma recurrent after surgery.Methods: This randomized controlled study was conducted on 38 women having recurrence of endometrioma after surgery. They were randomly assigned to receive either letrozole (2.5 mg daily) or dienogest (2 mg once daily) for 6 months. Size of the endometrioma was measured by transvaginal ultrasound and the pain (dysmenorrhoea) was measured on a visual analog scale (VAS) of 0-10, prior to treatment and after 3 and 6 months of treatment.Results: The mean size of endometrioma was reduced from a baseline of 6.06±2.40 cm to 5.23±1.37 cm and to 4.59±1.25 cm after 3 and 6 months of treatment with letrozole. While with dienogest the reduction was from a baseline of 6.67±1.31 cm to 4.83±1.50 cm and to 3.80±1.34 cm after 3 and 6 months of treatment. The difference between the two groups was not statistically significant but dienogest yielded better result in terms of effect size. Decrease in pain (dysmenorrhoea) was highly significant with both the drugs.Conclusions: In terms of reduction of the size of endometrioma, dienogest yields better results than letrozole. Both the drugs are highly effective in alleviating pain (dysmenorrhoea)

Vitamin D Supplementation in women with Diminished Ovarian Reserve: A Randomized Controlled Trial

Background: Diminished ovarian reserve (DOR) predicts decreased ovarian response to stimulation. Low serum anti-Mullerian hormone (AMH) is associated with DOR. AMH is a marker of ovarian reserve and acts as a predictor of ovarian response to ovarian stimulation protocol. The AMH is up regulated by vitamin D via vitamin D response elements that bind the vitamin D receptor. Vitamin D supplementation has a role in increasing serum AMH. The objective was to compare the combined effect of vitamin D and DHEA vs DHEA alone on serum AMH in DOR.  Methods: This randomized controlled trial was conducted in the Department of Reproductive Endocrinology and Infertility, Bangabandhu Sheikh Mujib medical University (BSMMU), Dhaka, from March 2021 to February 2022. A total of 44 infertile women with DOR, 20 to 39 years were allocated into two groups, one received vitamin D plus DHEA for 8 weeks and the other received DHEA alone for the same duration. After 8 weeks of treatment, both groups had repeat assessment of AMH, FSH and transvaginal sonography for AFC. Results: There was no significant difference in serum AMH after vitamin D supplementation in women with DOR. But the spontaneous pregnancy during intervention was 2.57 times more in those given vitamin D supplementations in addition to dehydroepiandrosterone (DHEA).Conclusions: Short term vitamin D supplementation adds little to the effect of increasing AMH but favors spontaneous pregnancy in women with DOR

Propuesta de virtualización de servidores con Hyper-V en el centro de datos de la Facultad de Ciencias Médicas de la UNAN-Managua

La importancia del crecimiento en la potencia de cómputo y la existencia de problemas relacionados con el uso del hardware, ha hecho de la virtualización la solución más idónea para resolver tales dificultades, dentro de sus propósitos se encuentran hacer uso eficiente de los recursos y disminuir el costo total asociado a los mismos. Este trabajo de investigación fue realizado con la finalidad de proponer una solución para la virtualización servidores. La virtualización es una tecnología que permite la creación de equipos, basados en software, que reproducen el ambiente de una máquina física en sus aspectos de CPU, memoria, almacenamiento y entrada y salida de dispositivos. Se limita a trabajar básicamente con Hyper-V con el fin de acotar y definir la solución de virtualización , debido a la numerosa cantidad de soluciones que existen actualmente, como lo son VMware, Cytrix, entre otros. El enfoque principal se encontrará relacionado principalmente a la virtualización de servidores, a la disposición de Hyper-V para trabajar en cluster y al tipo de cluster que se puede implementar. El objetivo general de este trabajo es entonces, proponer una solución para efectuar la virtualización ya manera explicativa se describe como trabaja un cluster de alta disponibilidad con Hyper-V para efectuar tareas de migración de maquinas virtuales, empleando técnicas propias que vienen incorporadas en el software, como Live Migration ó Quick Migration que facilitan de gran forma la gestión y administración del entorno virtual. También se describirá brevemente los detalles técnicos para la implementación del centro de datos, la disposición de las áreas funcionales, el diagrama de distribución y otros parámetros importantes a tenerse en cuenta para disponer de un centro de datos confiable

ASSIGN: Context-Specific Genomic Profiling of Multiple Heterogeneous Biological Pathways

Motivation: Although gene-expression signature-based biomarkers are often developed for clinical diagnosis, many promising signatures fail to replicate during validation. One major challenge is that biological samples used to generate and validate the signature are often from heterogeneous biological contexts—controlled or in vitro samples may be used to generate the signature, but patient samples may be used for validation. In addition, systematic technical biases from multiple genome-profiling platforms often mask true biological variation. Addressing such challenges will enable us to better elucidate disease mechanisms and provide improved guidance for personalized therapeutics. Results: Here, we present a pathway profiling toolkit, Adaptive Signature Selection and InteGratioN (ASSIGN), which enables robust and context-specific pathway analyses by efficiently capturing pathway activity in heterogeneous sets of samples and across profiling technologies. The ASSIGN framework is based on a flexible Bayesian factor analysis approach that allows for simultaneous profiling of multiple correlated pathways and for the adaptation of pathway signatures into specific disease. We demonstrate the robustness and versatility of ASSIGN in estimating pathway activity in simulated data, cell lines perturbed pathways and in primary tissues samples including The Cancer Genome Atlas breast carcinoma samples and liver samples exposed to genotoxic carcinogens. Availability and implementation: Software for our approach is available for download at: http://www.bioconductor.org/packages/release/bioc/html/ASSIGN.html and https://github.com/wevanjohnson/ASSIGN